The overall goal of this research plan is to design real proteins. This plan has four principal aims: (AIM 1) uncover what governs the designability of protein structures; (AIM 2) design proteins with a realistic matrix of interactions between amino acids; (AIM 3) design proteins taking into account the effect of side chains; (AIM 4) devise experimental in vitro tests of the designed proteins. A "design machine", a set of rapid algorithms which search for the protein sequence that folds into a target 3-dimensional conformation, is to be developed. To perform the search in the sequence space, the Monte Carlo algorithm will be deployed. To rapidly test the folding properties of the design protein, the Discrete Molecular Dynamics algorithm will be deployed. The selected candidate proteins will be put through additional tests, such as traditional Molecular Dynamics with all-atom representation of the protein. The last and the most crucial step will be to devise in vitro tests for the folding properties of the designed sequences. The specific protein motif, type III repeat, which is of particular interest for various clinical applications, will be used as a target structure in the design procedure. The ultimate long term research goal of my research is the solution of the direct and inverse folding problems. Specifically, the ultimate goal of this research is the design of the type III repeat.